The present invention relates to novel heterocyclic compounds. The compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of the serotonine 5-HT6 receptor.
Serotonin (5-hydroxytryptamine, 5HT), a monoamine neurotransmitter and local hormone, is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration is found in the enterochromaffin cells of the gastrointestinal tract, the remainder being predominantly present in platelets and in the Central Nervous System (CNS). 5HT is implicated in a vast array of physiological and pathophysiological pathways. In the periphery, it contracts a number of smooth muscles and induces endothelium-dependent vasodilation. In the CNS, it is believed to be involved in a wide range of functions, including the control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.
Neurons that secrete 5HT are termed serotonergic. The function of 5HT is exerted upon ist interaction with specific (serotonergic) neurons. Until now, seven types of 5HT receptors have been identified: 5HT1 (with subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E and 5HT1F), 5HT2 (with subtypes 5HT2A, 5HT2B and 5HT1C), 5HT3, 5HT4, 5HT5 (with subtypes 5HT1A and 5HT1B), 5HT6 and 5HT7). Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cγ.
The human 5HT6 receptors are positively coupled to adenylyl cyclase. They are distributed throughout the limbic, striatal and cortical regions of the brain and show a high affinity to antipsychotics.
The modulation of the 5HT6 receptor by suitable substances is expected to improve certain disorders including cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowl Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, drug addiction and obesity.
Another neurotransmitter with implications on the CNS is dopamine. Disorders in the dopaminergic transmitter system result in diseases of the central nervous system which include, for example, schizophrenia, depression and Parkinson's disease. These diseases, and others, are treated with drugs which interact with the dopamine receptors.
The dopamine receptors are divided into two families. On the one hand, there is the D2 group, consisting of D2, D3 and D4 receptors, and, on the other hand, the D1 group, consisting of D1 and D5 receptors. Whereas D1 and D2 receptors are widely distributed, D3 receptors appear to be expressed regioselectively. Thus, these receptors are preferentially to be found in the limbic system and the projection regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions, such as the amygdala. Because of this comparatively regioselective expression, D3 receptors are regarded as being a target having few side-effects and it is assumed that while a selective D3 ligand would have the properties of known antipsychotics, it would not have their dopamine D2 receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D3 Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347, 146 (1990)).
Compounds having an affinity for the dopamine D3 receptor have been described in the prior art on various occasions, e.g. in WO 95/04713, WO 96/23760, WO 97/45503, WO 99/58499 and in the unpublished international patent application PCT/EP 2005/011106.
Compounds having an affinity for the 5HT6 receptor have also been described in the prior art, e.g. in WO 2005/037830, WO 2005/026125, WO 00/05225 and WO 98/27081. However, their affinity and selectivity towards the 5HT6 receptor or their pharmacological profile is not yet satisfactory.
It is an object of the present invention to provide compounds which have a high affinity and selectivity for the 5HT6 receptor and optionally a high affinity and selectivity (in particular versus D2) for the dopamine D3 receptor, thus allowing the treatment of disorders related to or affected by the 5HT6 receptor. Compounds having an affinity for both receptors are expected to be suitable for treating disorders related to or affected by both the 5HT6 receptor and the D3 receptor, thus allowing the treatment of more than one aspect of the respective disorder.
The compounds should also have good pharmacological profile, e.g. a good brain plasma ratio, a good bioavailability, good metabolic stability, or a decreased inhibition of the mitochondrial respiration.